Alcoholism is a pharmacogenomic disease in which multiple genes each make modest contribution, but interact to render relative protection or relative vulnerability from deleterious consequences of alcohol use. A detailed understanding of the polygenetic contributions to alcoholism can provide the basis for developing pharmacogenomics-based treatment strategies for alcohol-related problems. This grant application focuses on the development of naturally occurring, or naturalistic rhesus monkey models of the human neurogenetic variance underlying alcoholism. The concept of naturalistic modeling of genetic variances is borne out of our findings of novel functional polymorphisms in rhesus monkeys that, although consisting of different alleles than occur in humans, nevertheless share common function and phenotypic association with polymorphisms in orthologous human genes implicated in neuropsychiatric and substance abuse disorders (Miller et al, 2001 b;2002;2004;2005). Accordingly, we predict that rhesus monkeys which harbor an array of unctionally parallel allelic variants to those implicated in human alcoholism could be utilized to clarify the genetic interactions influencing disorder variance, and could serve as a preclinical platform for the development of individualized, pharmacogenomics-based treatment interventions. In this regard, naturalistic modeling of the human neurogenetic variance associated with alcoholism in rheus monkeys would represent the first nonhuman primate model of a polygenetic disorder vulnerability. Our Aims are: 1) to identify novel rhesus monkey allelic variants of OPRM1, rhSHTTLPR, rhMAOA-LPR, TPH2 and NACP (alpha-synuclein);2) to functionally assess identified polymorphisms in OPRM1, rhSHTTLPR, rhMAOA-LPR, TPH2, and NACPREP1 in vitro in comparison to human variants;and 3) to develop genotyping assays for identified functional alleles, genotype NEPRC rhesus monkeys and generate lead data on genotype/phenotype relationships in phenotypically characterised rhesus monkeys at NEPRC. Our long-term ambition is to select cohorts of rhesus monkeys that harbor overlapping yet distinct constellations of disorder-related alleles that mimic in effect human polygenetic variance underlying the phenotypes, behaviors and traits associated with alcoholism. Through the accumulation of multiple shared genotype/phenotype components, naturalistic modeling of human neurogenetic variance in rhesus monkeys can be achieved.